Human Immunodeficiency Virus (HIV) is a retrovirus which is the etiological agent for acquired immune deficiency syndrome (AIDS) and a spectrum of related disorders (Coffin). The virus is transmitted by parenteral inoculation and/or intimate sexual contact. It is estimated that approximately 2 million people in the United States are infected with HIV at present, and current projections are that a majority of those now infected will develop AIDS or a significant clinical AIDS-related disease within a 7-10 year follow-up period (Barnes).
HIV is tropic and cytopathic for peripheral blood cells which express the cell surface differentiation antigen CD4 (T4, leu3). The viral tropism is believed to result from interactions between CD4 and the envelope glycoprotein of HIV. These interactions appear to be involved in the process by which HIV infects susceptible cells, and also underlie the mechanism by which HIV induces cell fusion in T cells (Lifson, 1986a, 1986b; Dalgleish; Klatzman, 1984a, 1984b; Maddon; McDougal, 1985a, 1085b; Sodroski). The cell fusion process, which leads to cell death, may, in turn, contribute to the progressive depletion of CD4 cells which charaterizes AIDS, and which is likely to be a major factor contributing to HIV-induced immunocompromise and its secondary consequences, opportunistic infections and neoplasms (Fahey).
The host cell range for the HIV virus includes, in addition to CD4+T cells, cells of the mononuclear phagocytic lineage, including peripheral blood monocyte/macrophages (Crowe; Gartner, 1986a, 1986b; Koenig; Ho; Chayt; Armstrong; Steicher), Langerhans cells of the skin, and dendritic reticulum cells within the lymph nodes. Mononuclear phagocytes may be a primary target cell for HIV infection within the central nervous system (Koenig; Gartner, 1986b). Cells of the macrophage lineage are likely to represent a major viral reservoir in vivo, and through their interactions with T cells, may contribute to the development and pathogenesis of AIDS and related clinical diseases (Crowe). Experiments conducted in support of the present invention suggest that a large percentage of monocyte/macrophages derived from HIV-infected individuals are capable of expressing HIV antigens, indicating widespread infection of the macrophage precursors. There is also evidence that macrophages expressing the HIV surface antigen may interact and fuse with CD4+T cells, leading to destruction of the crucial T cells (Crowe).
Intensive efforts to develop therapies which can prevent or block the development of serious clinical symptoms in HIV-infected individuals are under way. For the most part, these efforts have focused on the use of nucleotide analogue drugs which inhibit reverse transcriptase activity in virus-infected cells (Yarochan, 1986, 1987; Broder). These drugs would be expected to selectively inhibit new viral infection of cells, such as T cells and monocyte/macrophages, since reverse transcriptase is required for early viral infection. However, once viral infection is established in a cell, and viral replication is then carried out using host cell enzymes, the reverse transcriptase inhibitors would be expected to have limited inhibitory effect on viral replication and expression of viral antigens on the host cell surface. Although indications of some beneficial clinical effects have been observed, the early clinical testing results have provided little evidence that these drugs will be effective against later-stage progression of HIV infection to serious clinical diseases.